EP1194580B2 - Reconstitution in vitro de virus a arn de polarite negative segmentes - Google Patents

Reconstitution in vitro de virus a arn de polarite negative segmentes Download PDF

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EP1194580B2
EP1194580B2 EP00946097A EP00946097A EP1194580B2 EP 1194580 B2 EP1194580 B2 EP 1194580B2 EP 00946097 A EP00946097 A EP 00946097A EP 00946097 A EP00946097 A EP 00946097A EP 1194580 B2 EP1194580 B2 EP 1194580B2
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cells
virus
influenza
vrna
viral particles
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EP1194580A1 (fr
EP1194580B1 (fr
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George Gow University Of Oxford Brownlee
Ervin University Of Oxford Fodor
Peter Mount Sinai School Of Med. Ny Uni. Palese
Adolfo M. Sinai Sch. Med. Ny Uni. Garcia-Sastre
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Icahn School of Medicine at Mount Sinai
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
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    • A61K2039/5256—Virus expressing foreign proteins
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    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20051—Methods of production or purification of viral material
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    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16151—Methods of production or purification of viral material
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    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16161—Methods of inactivation or attenuation

Definitions

  • the present invention relates to reconstitution (rescue) of influenza A virus in cultured cells from recombinant DNAs. More particularly, it relates to rescue of influenza A virus having generally 8 genomic vRNA segments, by an entirely vector-driven system, which avoids the need for a helper virus.
  • Influenza remains a constant worldwide threat to human health and hence there is a particular need for a ready method of generating modified influenza viruses with known mutations in any of the genomic vRNA segments.
  • Engineering of influenza vRNA segments for expression of heterologous sequences is also of much interest, for example, in the development of new vaccines effective against influenza virus and a second pathogenic agent.
  • Three types of influenza virus are known designated as types A, B and C.
  • influenza A has been the main focus of attention as regards genetic manipulation.
  • the genome of a wild-type influenza A virus consists of 8 segments of single-stranded negative sense RNA which encode 10 polypeptides: the RNA-dependent RNA polymerase proteins (PB 1, PB2, and PA), the nucleoprotein (NP), the matrix proteins (M1, M2), two surface glycoproteins which project from the lipoprotein envelope (haemagglutinin (HA) and neuraminidase (NA)) and the non-structural proteins NS1 and NS2.
  • the HA, NA, NP and polymerase proteins are encoded by monocistronic genomic segments.
  • RNA viruses As for other segmented negative-strand RNA viruses, during the replication cycle of an influenza virus the viral genome is transcribed into mRNA and replicated into complementary RNA (cRNA). For this the genomic vRNA segments need to be complexed with the nucleoprotein and RNA-dependent RNA polymerase in ribonucleoprotein (RNP) complexes ( Huang et al., J. Virol. (1990) 64, 5669-5673 ; Garc ⁇ a-Sastre, Trends In Biotechnology (1998) 16, 230-235 ).
  • RNP ribonucleoprotein
  • RNPs were reconstituted in vitro from RNA transcribed from plasmid DNA in the presence of the polymerase proteins PB1, PB2 and PA and the nucleoprotein isolated from purified influenza virus ( Enami et al., Proc. Natl. Acad. Sci. USA (1990) 87, 3802-3805 ; Enami and Palese, J. Virol. (1991) 65, 2711-2713 ; Muster and Garcia-Sastre, Genetic manipulation of influenza viruses in Textbook of influenza (1998), ch. 9 , eds. Nicholson et al.).
  • the in vitro reconstituted RNPs were transfected into cells infected with a helper influenza virus, which provided the remaining required viral proteins and RNA segments, resulting in generation of transfectant viruses.
  • This technique has been extremely useful in advancing understanding of the molecular biology and pathogenicity of influenza viruses. However, it relies on highly specialised selection methods to isolate the transfectant viruses from the helper virus, which restricts its use to certain RNA segments of a limited number of viral strains.
  • influenza A PB 1, PB2, PA and NP expressed from plasmids could encapsidate, transcribe and replicate an influenza virus vRNA-like RNA containing a chloramphenicol acetyltransferase (CAT) reporter gene in transfected human 293 cells.
  • This vRNA-like reporter gene was introduced into the chosen host cells by transfection of a plasmid DNA (pPOLI-CAT-RT) having a truncated human RNA polymerase I promoter (nucleotides -250 to -1) positioned upstream of the vRNA-coding region.
  • the sequence of the hepatitis delta virus genomic ribozyme was positioned downstream of the vRNA-coding region in order to ensure RNA processing to give the correct 3' end of the transcribed vRNA. It was also reported by the same group that by replacing the plasmid encoding the CAT reporter gene with a plasmid encoding an authentic influenza A vRNA segment, intracellularly reconstituted RNP complexes could be rescued into transfectant viruses upon infection of the transfected cells with an influenza helper virus. Such a helper virus-based rescue system was investigated by Pleschka et al. employing intracellularly transcribed mutant influenza A NA vRNA segments. Moving to an entirely plasmid-based rescue system for influenza viruses raises, however, new considerations in terms of obtaining adequate expression of all the required sequences and the correct cooperation of those sequences to assemble a complete virus.
  • RNA viruses having a large number of genomic vRNA segments, for example 6 or more, including, for example, influenza viruses of other types and other members of the family Orthomyxoviridae such as the 6 vRNA segment-containing thogotoviruses. While both wild-type influenza A and influenza B viruses have 8 vRNA segments, modified influenza A viruses have been described containing an additional vRNA segment ( Enami et al., Virology (1993) 185, 765-90 ) and influenza C viruses have one less vRNA segment.
  • the present invention thus provides a method for generating infectious viral particles of an influenza A virus, said method comprising:
  • the chosen host cells may, for example, additionally have introduced one or more further expression vectors capable of directing expression in the cells of one or more of the required viral proteins.
  • a second set of expression vectors may be employed to express in the host cells all of the nucleoprotein and RNA-dependent polymerase subunits. Conveniently, for example, a separate expression vector for each of those proteins may be employed.
  • the chosen host cells may, for example, alternatively be engineered to express one or more of the required nucleoprotein and RNA-dependent RNA polymerase subunits. If all the essential proteins for encapsidation, transcription and replication of the vRNAs are provided by the starting host cells, then it will be appreciated that only the first set of expression vectors is required.
  • the chosen starting host cells may be cells engineered to express one or more of the genomic vRNAs segments of the desired virus.
  • the invention provides a method for generating in cultured cells infectious viral particles of an influenza A virus, said method comprising:
  • Viral particles produced by said first population of cells may be amplified by one or more further cellular infection steps, for example, employing cultured cells the same or different from said first population of cells.
  • the viral particles thus produced may be isolated.
  • Viral particles generated in accordance with the invention may be recombinant viral particles capable of expressing a heterologous sequence. Such particles, if necessary after attenuation or killing as appropriate, may also be formulated for vaccine use or other therapeutic purpose.
  • methods of the invention can easily be used for generation of infectious influenza virus of type A containing multiple mutations in several different genes at the same time.
  • Such a method also enables easier and more direct production of reassortant influenza A virus containing vRNA segments derived from more than one parent virus.
  • reassortant viruses are obtained by screening viral particles from a mixed viral infection of cells.
  • a method of the invention is particularly advantageous for production of reassortant influenza A virus which are difficult to isolate by classic methods.
  • Figure 1 is a schematic representation of an embodiment of the invention, as further described in Examples 1 to 3, in which 12 plasmids for direct expression of the vRNA segments of an influenza A virus and expression of influenza A nucleoprotein and RNA-dependent RNA polymerase subuints are cotransfected into cultured Vero cells (African green monkey kidney cells).
  • Vero cells African green monkey kidney cells
  • MDBK Mesh-Darby bovine kidney cells
  • POL I truncated human RNA polymerase I promoter
  • R genomic hepatitis virus ribozyme
  • MLP adenovirus type 2 major late promoter linked to a synthetic sequence comprising the spliced tripartite leader sequence of human adenovirus type 2
  • pA polyadenylation sequence from SV40.
  • genomic vRNA segments of influenza A virus may be entirely wild-type vRNA segments or may include at least one non-wild type vRNA segment, e.g. a mutant vRNA segment having one or more nucleotide substitutions, insertions or deletions.
  • At least one vRNA segment provided in the host cells may be a chimeric vRNA segment capable of expressing a sequence heterologous to the viral genome in target cells infected by the rescued virus.
  • a heterologous sequence may encode a peptide or a polypeptide. It may alternatively encode a nucleic acid such as a ribozyme or anti-sense nucleic acid.
  • the heterologous sequence may be provided on a vRNA segment additionally encoding a complete native viral protein as illustrated by the chimeric vRNA segment described in Example 8 or may be inserted into the coding sequence for a viral protein. For example, it is known that that the HA protein of influenza A can tolerate epitope-grafting in the antigenic site B.
  • the vRNA segments provided in the host cells may additionally or alternatively incorporate one or more attenuating mutations.
  • the vRNA segments may be the vRNA segments of an influenza A virus having an attenuating base pair substitution in a pan-handle duplex promoter region, in particular, for example, the known attenuating base pair substitution of A for C and U for G at position 11-12' in the duplex region of the NA-specific vRNA (Fodor et al., J. Virol. (1998) 6283-6290).
  • new attenuating mutations may be identified.
  • attenuation or killing of the viral particles may, however, be subsequently achieved, for example, by classic methods.
  • Attenuated or killed viruses produced in accordance with the invention may subsequently be incorporated into a vaccine composition in conventional manner.
  • a virus may be formulated to achieve vaccination against more than one pathogen simultaneously.
  • Attenuated recombinant viruses produced in accordance with the invention which possess a chimeric vRNA segment may also be designed for other therapeutic uses, e.g. an anti-tumour agent or gene therapy tool, in which case production of the virus will be followed by its incorporation into an appropriate pharmaceutical composition together with a pharmaceutically acceptable carrier or diluent.
  • helper-virus free rescue in accordance with the invention is particularly favoured for generation of reassortant viruses, especially reassortant influenza viruses desired for vaccine use.
  • the HA and NA vRNA segments of an influenza virus e.g. influenza A/PR8/34 which is recognized as suitable for human administration, may be readily substituted with the HA and NA vRNA segments of an influenza strain associated with an influenza infection epidemic.
  • Such reassortant influenza viruses may, for example, be used for production of a killed influenza vaccine in conventional manner (see Examples 4 and 6).
  • the expression vectors employed may preferably be plasmids capable of replication in the chosen host cells.
  • a separate expression vector may be provided for direct expression of each required vRNA segment or the corresponding cRNA.
  • a second set of expression vectors may also be provided for each of the nucleoprotein and the individual RNA-dependent RNA polymerase subunits, e.g. the PB1, PB2 and PA subunits of an influenza virus RNA-dependent RNA polymerase.
  • a cell line may be employed which is capable of expressing one or more of these proteins in which case the second set of expression vectors may be reduced or even eliminated.
  • Example 7 illustrates such a method for helper virus-free rescue of an influenza A virus employing a cell line stably expressing the nucleoprotein.
  • All the required expression vectors may preferably be introduced into the chosen host cells in a single cotransfection or cotransduction step.
  • liposomal transfection may preferably be employed, for example using DOTAP liposomal transfection reagent (Boehinger Mannheim) or LipofectAMINE 2000 (Gibco BRL).
  • vector transfer step may be carried out and other known means for introduction of vectors into mammalian cells employed, for example, electroporation, DEAE-dextran transfection, microparticle-bombardment and viral transduction, e.g. use of replication-defective retroviruses.
  • Calcium phosphate preciptation is also particularly preferred (see Example 5). It may be chosen for example, to introduce into the host cells expression vectors for expression of the NP and polymerase proteins before the expression vectors for expression of the vRNA segments.
  • the host cells into which the required vectors are introduced may be in a culture dish or cultured in other appropriate ways for vector transfection or transduction.
  • RNA Pol I promoter a promoter sequence derived from a mammalian RNA Pol I promoter. Particularly preferred for this purpose is the truncated human RNA Pol I promoter consisting of nucleotides -250 to -1 of the corresponding native promoter or a functional derivative thereof ( Jones et al., Proc. Natl. Acad. Sci. USA (1988) 85, 669-673 ).Other promoters may, however, alternatively be employed, including, for example, a T7 RNA polymerase promoter.
  • each vRNA or cRNA expression vector will incorporate a ribozyme sequence or appropriate terminator sequence downstream of the RNA coding sequence.
  • a ribozyme sequence or appropriate terminator sequence may be, for example, the hepatitis delta virus genomic ribozyme sequence or a functional derivative thereof Alternatively, for example, a Pol I terminator may be employed ( Neumann et al., Virology (1994) 202, 477-479 ).
  • the RNA expression vectors may be constructed in the same manner as the vRNA expression vectors described in Pleschka et al., J. Virol.(1996) 70, 4188- 4192 .
  • one or more protein expression vectors are required to express viral proteins for RNP complex formation, these will preferably express the required viral protein(s) homologous to the desired virus.
  • Expression of the nucleoprotein and RNA-dependent polymerase subunits may preferably, for example, be under the control of a regulatory sequence comprising the adenovirus 2 major late promoter linked to the spliced tripartite leader sequence of human adenovirus type 2, as described by Berg at al., BioTechniques, 14, 972-978 , or a functional derivative of said regulatory sequence.
  • promoter sequences operative in mammalian cells may possibly be substituted such as, for example, another viral promoter such as, for example, the human cytomegalovirus (CMV) immediate-early promoter or a T7 polymerase promoter.
  • CMV human cytomegalovirus
  • Appropriate plasmids for expression of the NP and polymerase subunits may be constructed, for example, starting from the plasmid pGT-h as also described in the above-noted paper of Berg et al.
  • influenza A rescue by the strategy of the invention utilising plasmids which directly express the required vRNAs, it has been found favourable, for example, to use Vero (African green monkey kidney) cells, although other cells which support growth of influenza viruses may be employed, for example, preferably 293T human embryonic kidney cells (293T cells are disclosed herein for technical reference). Such cells may be transfected preferably on the surface of an appropriate culture dish.
  • Vero African green monkey kidney
  • 293T cells 293T human embryonic kidney cells
  • Vero cells are deficient in interferon expression ( Diaz et al., Proc. Natl. Acad. Sci. USA (1998) 85 5259-5263 ), which might be a factor in attaining good viral rescue. Hence, it is extrapolated that Vero cells and other cells deficient in interferon activity or response which will support growth of segmented negative-strand RNA viruses are useful in the practice of the invention.
  • each plasmid may be employed at a few ⁇ gs, e.g 1 to 10 ⁇ g, for example, diluted to a final total DNA concentration of about 0.1 ⁇ g/ml prior to mixing with transfection reagent in conventional manner. It may be preferred to use vectors expressing NP and/or RNA-dependent RNA polymerase subunits at a higher concentration than those expressing vRNA segments.
  • the present specification also provides a method for generating in cultured cells infectious viral particles of an influenza A virus said method comprising:
  • virus-producing cells may, for example, preferably be Vero cells or other cells deficient in interferon activity or response which will support the growth of a segmented negative-strand RNA virus. All or some of the coding sequences for said genomic vRNAs, nucleoprotein and RNA-dependent RNA polymerase may be provided in the chose host cells by introducing expression vectors into the cells.
  • plasmids each expressing a different vRNA segment of influenza A/WSN/33 were used (pPOL1-PB2-RT, pPOL1-PB1-RT, pPOL1-PA-RT, pPOL1-HA-RT, pPOLI-NP-RT, pPOL1-NA-RT, pPOL1-M-RT and pPOL1-NS-RT).
  • pPOL1-PB2-RT pPOL1-PB1-RT
  • pPOL1-PA-RT pPOL1-HA-RT
  • pPOLI-NP-RT pPOL1-NA-RT
  • pPOL1-M-RT pPOL1-NS-RT
  • Samples of influenza A/WSN/33 for preparation of the cDNA inserts of the above-described plasmids are obtainable, for example, from the W.H.O. Collaborating Centre, Division of Virology, National Institute for Medical research, London, U.K.)
  • the pGT-h set of protein expression plasmids was constructed by inserting the open reading frames for the PB1, PB2, PA and NP proteins into the Bcl I cloning site of the pGT-h plasmid (Berg et al. (1993), ibid. )
  • the expression plasmids encoding the viral nucleoprotein and 3 protein subunits of the viral RNA-dependent RNA polymerase were cotransfected into human 293 cells or Vero cells with the expression plasmid pPOL1-CAT-RT. In both the transfected human 293 cells and Vero cells, CAT activity could be detected. Vero cells were chosen for helper-virus free generation of influenza A/WSN/33 from transfected vRNA segments as further described below since they support better growth of influenza A/WSN/33 than human 293 cells (about one log difference in maximum viral titre).
  • the transfection mixture was incubated at room temperature for 15 mins and then mixed with 6.5 ml of Minimal Essential Medium (MEM) containing 0.5% fetal calf serum (FCS), 0.3% bovine serum albumin (BSA), penicillin and streptomycin. This mixture was added to the Vero cells washed with PBS. After 24 hours, the transfection medium was removed from the cells and replaced with 8 ml of fresh medium (MEM) containing 0.5% FCS, 0.3% BSA, penicillin and streptomycin. The transfected Vero cells were cultured for at least 4 days after transfection.
  • MEM Minimal Essential Medium
  • FCS fetal calf serum
  • BSA bovine serum albumin
  • penicillin and streptomycin penicillin and streptomycin
  • the medium from the transfected cells was collected and assayed for the presence of influenza virus by plaquing a 0.5 ml aliquot on MDBK cells in conventional manner.
  • the rest of the medium was transferred into 75 cm 2 flasks of subconfluent MDBK cells for amplification of any rescued virus.
  • the original transfected cells were further incubated after adding 8 ml of fresh medium.
  • plaque-forming viral particles were obtained from a 8.5 cm dish containing approximately 10 7 cells.
  • the rescued virus showed a specific property characteristic of influenza A/WSN/33 virus, i.e. it formed plaques on MDBK cells in the absence of trypsin.
  • the plaques formed by the rescued virus were comparable in size to those formed by a control authentic A/WSN/33 virus sample grown on the same MDBK cells.
  • a cDNA was constructed encoding an HA vRNA segment with a mutation of 6 nucleotides near the 3' end of the segment. Nucleotides 31 to 35 from the 3' end (3'-UUUUG-5') were replaced with 3'-AAAAC-5' resulting in amino acid substitution at amino acid 4(K ⁇ F) and at amino acid 5 (L ⁇ V) near the N-terminus of HA within the signal peptide. In addition, a silent C ⁇ U mutation was created at nucleotide 40.
  • the cDNA encoding the NA segment was mutated to encode an NA segment containing two silent mutations at nucleotides 1358 and 1360 so as to introduce a new unique SacI restriction site ( Pleschka et al., J. Virol (1996) 70, 4188-4192 ).
  • vRNA Medium from MDBK cells infected with the rescued transfectant virus was used to isolate vRNA. 100 ⁇ l of the medium was treated with 5 u of RNase-free DNase to remove any residual plasmid DNA carried over. After 15mins at 37°C, vRNA was isolated using the RNeasy Mini Kit (Qiagen). Short regions of the HA and NA vRNAs expected to contain the genetic tags were amplified by RT-PCR and then analysed by digestion with SpeI and SacI restriction enzymes, respectively. As a control, the same regions of the HA and NA segments were amplified from vRNA isolated from authentic influenza A/WSN/33 virus using the same RT-PCR primers.
  • PCR products obtained from the rescued virus and the control virus were the same size. Those originating from the HA and NA segments of the rescued virus could be digested with SpeI and SacI respectively. However, the PCR products corresponding to the control virus were, as expected, not digested by the same enzymes. The omission of reverse transcriptase in control RT-PCR reactions resulted in no visible PCR products.
  • influenza virus was generated by expressing negative sense vRNA segments. This seems to contradict some earlier studies which emphasised the importance of using positive strand RNA for rescuing negative strand RNA viruses, including Bunyamwera virus whose genome is in 3 segments ( Schnell et al. (1994) EMBO J., 13, 4195-4203 ; Roberts and Rose (1998) Virology 247, 1-6 ; Bridgen and Elliot (1996) 93, 15400-15404 ). However, more recent successful recoveries of non-segmented negative-strand RNA viruses from negative sense RNA have been reported ( Kato et al.(1996) Genes Cells 1, 569-579 ; Durbin et al. (1997) Virology 235,323-332 ).
  • the 12 plasmids are analogous to those described for the rescue of A/WSN/33 virus (see Examples 1 and 2 above), with a few modifications.
  • the 8 plasmids required for the synthesis of the 8 vRNA segments, by cellular RNA Polymerase 1, have a murine rDNA terminator sequence (GenBank, accession number M12074) instead of the hepatitis delta virus ribozyme to generate the exact 3' end of the vRNA segments.
  • the 4 protein expression plasmids for the A/PR/8/34 polymerase subunits (PB1, PB1, PA) and the nucleoprotein (NP) are based on the commercially available pcDNA3 (Invitrogen, Catalogue No. V790-20), which has a cytomegalovirus (CMV) promoter and a bovine growth hormone (BGH) poly(A) site.
  • CMV cytomegalovirus
  • BGH bovine growth hormone
  • pPolISapIT a new basic cloning vector, pPolISapIT.
  • the murine rDNA terminator sequence (positions +572 to +715) is positioned downstream of the Pol I promoter.
  • the Pol I promoter and terminator sequences are separated by a 24 bp linker sequence (5'-AGAAGAGCCAGATCTGGCTCTTCC-3'), containing SapI restriction sites.
  • Plasmid pPolISapIT was derived from pPolI-CAT-RT (originally described in Pleschka et al., J. Virol. 70, 4188-4192, 1996 ).
  • a DNA fragment containing a region of the murine rDNA terminator sequence (positions +335 to +715, GenBank accession number M12074) was inserted into the SalI site of pPolI-CAT-RT to generate pPolI-CAT-T.
  • the CAT gene, the ribozyme and part of the murine rDNA terminator sequence were deleted from pPolI-CAT-T.
  • the 24 bp linker sequence as given above was introduced through the PCR primers between the Pol I promoter and the murine rDNA terminator sequence.
  • cDNA was generated by RT-PCR from vRNA isolated from influenza A/PR/8/34 virus (Cambridge variant) using PCR primers with SapI overhangs. After SapI digestion, the PCR products were cloned into pPolISapIT digested with SapI.
  • influenza A/PR8/34 virus can be successfully rescued by the helper virus-free method of the invention.
  • influenza A/PR8/34 is known to be avirulent to humans (Beare et al. (1975) Trials in man with live recombinants made from A/PR8/34 (HON1) and wild H3 N2 influenza viruses, Lancet (ii) 729-732) whereas influenza A/WSN/33 is considered unsuitable for administration to humans because of its known neurotropism in mice. It is thus proposed that influenza A/PR8/34, in a suitably attenuated form, would be suitable as a parent virus for live vaccine development.
  • helper virus-free viral rescue in accordance with the invention could be used to generate an attenuated reassortant virus starting with expression vectors for the vRNAs of influenza A/PR8/34 apart from substitution of the HA and NA genomic segments of A/PR8/34 virus with the HA and NA genomic segments of an influenza strain associated with an influenza infection epidemic.
  • helper-virus free viral rescue in accordance with the invention to generate reassortant influenza viruses is given in Example 6 below.
  • Example 2 The 4 protein expression plasmids specified in Example 2 were replaced with the protein expression plasmids specified in Example 4 derived from pcDNA3. Using these four protein expression plasmids together with the eight vRNA transcription plasmids specified in Example 1 (see also Fodor et al., J. Virol. (1999) 73 . 9679-9682) in the 3 protocols set out below, between 100-10,000 plaque-forming viral particles from 10 6 cells were obtained on day 2 post-transfection This is at least 100 times more virus than obtained by the transfection studies reported in Example 3.
  • the transfection mixture was removed and replaced with 1 ml of DMEM containing 0.5% FCS, 0.3% BSA, penicillin and streptomycin. 24-48 hours later, rescued virus was screened for by plaquing 100 ⁇ l of the medium from the transfected 293 T cells on MDBK cells and by passaging the rest of the medium on a 25 cm 2 semiconfluent MDBK flask. 1 ml of DMEM containing 0.5% FCS, 0.3% BSA penicillin and streptomycin was added to the transfected 293T cells and incubation continued for another 2 to 3 days before repeating the plaquing and amplification on MDBK cells.
  • transfection mixture was removed and replaced with 1 ml of DMEM containing 0.5% FCS, 0.3% BSA, penicillin and streptomycin. 24-48 hours later, rescued virus was screened for as in protocol (a) above.
  • the transfection mixture was removed and replaced with 1 ml of MEM containing 0.5% FCS, 0.3% BSA, penicillin, and streptomycin. 24-48 hours later, rescued virus was screened for by plaquing 100 ⁇ l of the medium from the transfected Vero cells on MDBK cells and by passaging the rest of the medium on a 25 cm 2 semiconfluent MDBK flask. 1 ml of MEM containing 0.5% FCS, 0.3% BSA, penicillin, and streptomycin was added to the transfected Vero cells and incubation continued for another 2 to 3 days before repeating the plaquing and amplification on MDBK cells.
  • Plasmid-based rescue in accordance with the invention has been successfully used to generate reassortant influenza viruses.
  • the following reassortant viruses were generated:
  • helper virus free method for isolating reassortants.
  • Reassortant viruses based on A/PR8/34 are required for the production of conventional killed vaccines because they grow to high titre in embryonated chicken eggs - used in the commercial production of killed influenza vaccines.
  • helper virus free viral rescue in accordance with the invention is thus seen to be easier and more direct isolation of reassortant viruses than by the classic method of isolating reassortants from a mixed infection of cells with two live viruses.
  • the need to screen many potential reassortants before the required one is isolated is obviated.
  • EcR-293NP cells were derived from the commercially available cell line EcR-293 (Invitrogen, Catalogue No. R650-07) which constitutively expresses the VgEcR and RXR. subunits of the ecdysone receptor. Influenza NP expression in such cells is inducible in response to ponasterone A.
  • the same protocol was used as specified in Example 5(a) employing LipofectAMINE 2000 transfection reagent except pcDNA-NP was omitted, since the NP protein for the initial encapsidation of the vRNA segments was provided by the EcR-293NP cells.
  • the plasmid pPOL1-E6N18-2A-NA was generated capable of expressing a chimeric vRNA segment based on the NA vRNA segment of influenza A/WSN/33 virus.
  • the modified vRNA coding sequence was inserted between sequences corresponding to a truncated human Pol I promoter and hepatitis delta virus ribozyme as for preparation of the Pol I-expression plasmids described in Example 1.
  • the resultant chimeric gene contained a long open reading frame (ORF) encoding the first 88 amino acids of the E6 protein of human papillomavirus 18 (HPV 18), followed by 17 amino acids corresponding to the self-cleavage motif of the 2A protease of foot-and-mouth-disease virus (FMDV), followed by the amino acid sequence of the NA of influenza A/WSN/33.
  • the coding region was flanked by the non-coding regions of the NA gene of A/WSN/33 virus. In this way, a chimeric influenza virus gene was generated encoding a polyprotein that undergoes self-cleavage, resulting in the generation of an HPV-derived polypeptide and the NA protein.
  • the recombinant influenza virus vector expressing the HPV18-derived antigen was generated by co-transfecting into 293T cells pPOL1-E6N18-2A-NA together with 7 PolI-expression vectors encoding wild-type viral RNAs, i.e. PB2, PB1, PA, HA, NP, M and NS as described in Example 1 and the 4 PolII-expression vectors encoding the PB2, PB 1, PA and NP proteins as described in Example 5.
  • the rescued virus had the correct nucleotide sequence as confirmed by sequence analysis of its NA-specific viral RNA.

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Claims (33)

  1. Procédé destiné à générer des particules virales infectieuses du virus de la grippe A, ledit procédé comprenant le fiait :
    d'introduire dans des cellules cultivées des vecteurs d'expression qui expriment dans lesdites cellules les segments d'ARNv génomiques complets dudit virus, où lesdites cellules soutiennent la croissance dudit virus, lesdites cellules fournissant également une nucléoprotéine et une ARN polymérase dépendante de l'ARN grâce à quoi des complexes RNP contenant les segments d'ARNv génomiques dudit virus sont formés et lesdites particules virales infectieuses sont produites par lesdites cellules en l'absence d'un virus assistant et où lesdites cellules ne produisent pas d'interféron.
  2. Procédé tel que revendiqué dans la revendication 1 dans lequel un ou plusieurs vecteurs d'expression supplémentaires sont utilisés dans lesdites cellules pour exprimer une ou plusieurs protéines sélectionnées de ladite nucléoprotéine et des sous-unités de ladite ARN polymérase dépendante de l'ARN.
  3. Procédé tel que revendiqué dans la revendication 1 ou 2 dans lequel une lignée cellulaire qui est capable d'exprimer une ou plusieurs de ladite nucléoprotéine et des sous-unités de ladite ARN polymérase dépendante de l'ARN est utilisée.
  4. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 3 dans lequel ledit virus est un virus réassorti ayant des segments d'ARNv dérivés de plus d'un virus parent.
  5. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 4 dans lequel lesdites cellules sont des cellules Vero.
  6. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 5 dans lequel lesdits vecteurs d'expression définis dans la revendication 1 expriment des segments d'ARNv génomiques dudit virus.
  7. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 6 comprend en outre l'amplification desdites particules virales formées par une ou plusieurs étapes d'infections cellulaires subséquentes en utilisant le même type de cellules ou un type de cellules différent.
  8. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 7 qui comprend en outre l'isolation de particules virales infectieuses.
  9. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 8 qui comprend en outre une étape d'élimination ou d'atténuation virales.
  10. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 9 dans lequel tous les vecteurs d'expression requis sont co-transfectés dans lesdites cellules en utilisant un réactif de transfection liposomale, une électroporation ou une précipitation de phosphate de calcium.
  11. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 10 dans lequel lesdits vecteurs d'expression sont tous des plasmides.
  12. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 11 dans lequel lesdits vecteurs d'expression définis dans la revendication 1 se composent de vecteurs d'expression séparés pour l'expression de chaque segment d'ARNv dudit virus.
  13. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 12 dans lequel l'expression de chaque segment d'ARNv est sous le contrôle d'une séquence promotrice dérivée d'un promoteur de Poll d'un mammifère.
  14. Procédé tel que revendiqué dans la revendication 13 dans lequel ladite séquence promotrice est une séquence de promoteur de Poll humain tronquée constituée de nucléotides -250 à -1 du promoteur natif correspondant ou d'un dérivé fonctionnel de celui-ci.
  15. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 14 dans lequel la séquence de codage pour chaque segment d'ARNv dans lesdits vecteurs d'expression est suivie par une séquence de ribozyme ou un terminateur de transcription qui produit une extrémité 3' correcte de chaque dit ARN.
  16. Procédé tel que revendiqué dans la revendication 2 dans lequel l'expression d'une ou de plusieurs protéines virales desdits vecteurs d'expression supplémentaires est sous le contrôle d'une séquence régulatrice sélectionnée du promoteur tardif majeur de l'adénovirus de type 2 lié à la séquence de tête tripartite épissée de l'adénovirus humain de type 2 ou du promoteur précoce-immédiat du cytomégalovirus humain, ou d'un dérivé fonctionnel de ladite séquence régulatrice.
  17. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 16 qui comprend en outre l'incorporation d'un virus tué ou atténué dans une composition de vaccin.
  18. Procédé tel que revendiqué dans l'une quelconque des revendications 1 à 17 dans lequel ledit virus a au moins un segment d'ARNv capable de diriger l'expression d'une séquence hétérologue audit virus dans des cellules cibles infectées par ledit virus.
  19. Procédé tel que revendiqué dans la revendication 18 dans lequel ladite séquence hétérologue audit virus code un peptide antigénique ou un polypeptide antigénique et qui comprend en outre l'incorporation dudit virus dans une composition de vaccin.
  20. Cellules modifiées telles que produites dans la revendication 1 ou 5.
  21. Procédé pour produire des particules virales infectieuses d'un virus à polarité négative segmenté qui comprend la culture des cellules modifiées telles que revendiquées dans la revendication 20.
  22. Procédé pour générer dans des cellules cultivées des particules virales infectieuses du virus de la grippe A, ledit procédé comprenant le fiait :
    de fournir une première population de cellules qui sont capables de soutenir la croissance dudit virus et qui ont été modifiées afin de fournir (a) les ARNv génomiques dudit virus et (b) une nucléoprotéine et une ARN polymérase dépendante de l'ARN grâce à quoi des complexes RNP contenant lesdites ARNv génomiques sont formés et lesdites particules virales infectieuses sont assemblées, lesdites ARNv génomiques sont directement exprimées dans lesdites cellules sous le contrôle d'un promoteur de Poll d'un mammifère ou d'un dérivé fonctionnel de celui-ci en l'absence d'un virus assistant, et où lesdites cellules de produisent pas d'interféron.
  23. Procédé de la revendication 22 comprenant en outre l'amplification desdites particules virales assemblées par une ou plusieurs étapes d'infections cellulaires subséquentes utilisant le même type de cellules ou un type de cellules différent.
  24. Procédé tel que revendiqué dans la revendication 22 ou 23 qui comprend en outre l'isolation des particules virales infectieuses.
  25. Procédé tel que revendiqué dans l'une quelconque des revendications 22 à 24, qui comprend en outre une étape d'élimination ou d'atténuation virale.
  26. Procédé tel que revendiqué dans l'une quelconque des revendications 22 à 25 qui comprend en outre l'incorporation de particules virales tuées ou atténuées dans une composition de vaccin.
  27. Procédé tel que revendiqué dans l'une quelconque des revendications 22 à 25 dans lequel ledit virus a un segment d'ARNv au moins capable de diriger l'expression d'une séquence hétérologue audit virus dans des cellules cibles infectées par ledit virus et qui comprend en outre l'incorporation dudit virus, si cela est approprié après atténuation ou élimination, dans une composition pharmaceutique conjointement avec un diluent ou un porteur pharmaceutiquement acceptable.
  28. Procédé tel que revendiqué dans l'une quelconque des revendications 22 à 27, dans lequel lesdites cellules sont des cellules Vero.
  29. Cellules modifiées telles que produites dans la revendication 22 ou 28.
  30. Procédé pour produire des particules virales infectieuses d'un virus à polarité négative segmenté qui comprend la culture de cellules modifiées telles que revendiquées dans la revendication 29.
  31. Procédé de l'une quelconque des revendications 7 à 15 et 17 à 19 dans lequel les cellules utilisées pour amplification sont des cellules MDBK ou des cellules MDCK.
  32. Procédé de l'une quelconque des revendications 23 à 28, dans lequel les cellules utilisées pour amplification sont des cellules MDBK ou des cellules MDCK.
  33. Procédé des revendications 1 à 19, 21 à 28 ou 30 à 32, dans lequel les cellules sont des cellules EcR-293NP.
EP00946097A 1999-07-14 2000-07-14 Reconstitution in vitro de virus a arn de polarite negative segmentes Expired - Lifetime EP1194580B2 (fr)

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JOP20190256A1 (ar) 2017-05-12 2019-10-28 Icahn School Med Mount Sinai فيروسات داء نيوكاسل واستخداماتها
EP3921413A1 (fr) 2019-02-08 2021-12-15 Wisconsin Alumni Research Foundation (WARF) Lignée cellulaire humanisée
US11807872B2 (en) 2019-08-27 2023-11-07 Wisconsin Alumni Research Foundation (Warf) Recombinant influenza viruses with stabilized HA for replication in eggs
CN111363727B (zh) * 2020-01-20 2021-09-24 武汉大学 携带幽门螺杆菌的重组流感病毒、宿主细胞及其制备方法与应用
EP3896077A1 (fr) 2020-04-16 2021-10-20 Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbH Particules de type virus de la grippe

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US5840520A (en) * 1989-08-28 1998-11-24 Aviron Recombinant negative strand RNA virus expression systems
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NL300369I1 (nl) 2009-01-05
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DE122007000070I1 (de) 2008-01-31
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CY1106404T1 (el) 2010-07-28
FR08C0046I1 (fr) 2009-01-02
DK1194580T3 (da) 2007-04-10
WO2001004333A1 (fr) 2001-01-18
NL300301I1 (nl) 2008-01-02
NL300368I1 (nl) 2009-01-05
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EP1194580A1 (fr) 2002-04-10
NL300301I2 (nl) 2008-10-01
DE122007000061I1 (de) 2007-12-20
DE122008000056I1 (de) 2009-04-09
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NL300294I2 (nl) 2008-10-01
CA2379012A1 (fr) 2001-01-18
NL300294I1 (nl) 2007-12-03
ES2278621T5 (es) 2011-02-02
CY2007023I1 (el) 2009-11-04
CA2379012C (fr) 2013-07-02
FR08C0046I2 (fr) 2011-11-25
DE122008000057I1 (de) 2009-04-09
NL300368I2 (nl) 2017-08-03
DE122007000061I2 (de) 2011-07-21
DK1194580T4 (da) 2011-01-03
DE60033284T3 (de) 2014-10-30
EP1194580B1 (fr) 2007-02-07
AU5998400A (en) 2001-01-30

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Free format text: CORRECTED ENTRY FOLLOWS; REASON FOR LAPSE IN JOURNAL 6879 - 24.03.2021 WAS PUBLISHED IN ERROR, THE REASON FOR LAPSE WAS FEES NOT PAID. ; APPLICANT: MOUNT SINAI SCHOOL OF MEDICINE OF NEW YORK UNIVERSITY; 1 GUSTAVE L. LEVY PLACE, NEW YORK, NY 10029, USA; PRODUCT: PANDEMIC INFLUENZA VACCINE, WHOLE VIRON INACTIVATED VIRUS OF A PANDEMIC INFLUENZA VIRUS STRAIN RECOMMENDED BY THE WHO-EU FOR THE PANDEMIC, ORIGINALLY OF A/VIETNAM/1194/2004 (H5N1); PRODUCT TYPE: MEDICINAL; AUTHORISED: UK EU/1/06/381/001 21 MARCH 2007; UK EU/1/06/381/002 21 MARCH 2007; UK EU/1/06/381/003 21 MARCH 2007; UK EU/1/06/381/004 21 MARCH 2007; UK EU/1/06/381/005 21 MARCH 2007; UK EU/1/06/381/006 21 MARCH 2007; UK EU/1/06/381/

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Free format text: PRODUCT NAME: PREPANDEMIC INFLUENZA VIRUS ANTIGENS OF PREPANDEMIC INFLUENZA VIRUS STRAIN RECOMMENDED BY THE WHO-EU FOR PREPANDEMIC USE, CURRENTLY THE A/INDONESIA/05/2005 (H5N1) LIKE STRAIN, PR8-IBCDC-RG2.; REGISTERED: UK EU/1/08/453/001 20080516

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Free format text: PRODUCT NAME: PANDEMIC SPLIT INFLUENZA VIRUS INACTIVATED, CONTAINING ANTIGEN EQUIVALENT TO A PANDEMIC INFLUENZA VIRUS STRAIN RECOMMENDED BY THE WHO-EU FOR THE PANDEMIC ORIGINALLY OF A/VIETNAM/1194/2004 (H5N1); REGISTERED: UK EU/1/08/452/001 20080522

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